TW200817005A - Aqueous formulation comprising an antitumor agent - Google Patents

Abstract

Disclosed are compositions and pharmaceutical formulations comprising (2R)-2-[4-(7-bromo-2-quinolyloxy)phenoxy]propanoic acid, and methods of use thereof.

Description

200817005 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to an active agent (2卟2-[4-(7|-yl)propionic acid' and especially relates to parenteral administration of oxime Linki) phenoxy]propionic acid or its medicinal "·- formulation. The novel medicine of the salt [the prior art] has been shown to have the structural formula (1) called 2_[4_(7_莫默基) Phenoxy]propionic acid: a territorial based milk (I), which is particularly advantageous as an anticancer agent. For example, U.S. Patent No. 6,867,219 (which is incorporated herein by reference in its entirety) Preparation, physical properties and beneficial pharmacological properties of _2 cases of 7_involved-2-oxooxy)propionyl]propionic acid. (2R)-2-[4-(7-演_2_ Wahlinyloxy)phenoxy]propionic acid is administered as a liquid parenteral formulation. (2R)-2-[4-(7-moly-2- 4 phenyl) was found in preliminary animal toxicology studies. Alkoxy)phenoxy]propionic acid causes a certain degree of hemolysis when infused as a single phosphate buffer formulation at 1 mg/mL or higher. Because significant hemolysis causes anemia, (2R) -2- [4-(7- desert The hemolysis of -2-mercaptooxy)phenoxy]propionic acid is a poor property for pharmaceutical compositions. 123610.doc 200817005 Needs to reduce the hemolysis caused by drugs (2R)_2_[4_(7 a compound of quinolyloxy)phenoxy]propionic acid. [Summary of the Invention] Several methods for hemolytic action induced by H drugs have been reported to be effective for certain drugs. For example, longer non- The infusion time of the enteral formulation (also decreasing the rate of transfusion or decreasing the concentration of the active drug) may result in a low activity of the active drug I. However, longer infusion times may undesirably result in decreased patient compliance. The method includes adding a tonicity agent, a surfactant, a colloidal osmoprotectant, an integrator/membrane stabilizer, an egg-based radical scavenger or a complexing agent (such as a cyclodextrin) to the towel. However, in vivo studies. Mainly limited to in vitro results but not confirmed live-blood: Benxin Ming has been thoroughly researched and found to reduce the blood-induced Luoxue effect (2R)_2_[4_(7_漠_2_ Improve%%% "ortmented with fluorenyl) phenyl] propionate . The cyclodextrin in the parenteral additive mixture studied is effective. - The zombie is called the wrong:: 'Dry dextrin can reduce the hemolysis caused by in vitro drugs, and the inner ring of a false sputum % dextrin can be separated from the red blood cells by the complex with the drug'. Incorporating for hemolysis, only the free music used for reading is less, so that the formula is raised. This mechanism can be applied to an in vitro test that maintains a portion of the drug as a mismatch: the member dilutes the drug solution (such as the virtual 01 float mixture described in most of the reports). However: during the 1|/main period, most of the sputum is rapidly and completely separated from the cyclodextrin cavity due to a large dilution of J23630.doc 200817005. This makes the invention unpredictable in vivo. Discovery · Adding to the pharmaceutical formulation of (2r-based) phenoxy] propionic acid, the odor is reduced - I quinolinyloxy is reduced in vivo (2 Han) - 244 ^ ^ plus % dextrin can be in vitro And hemolytic action induced by propionic acid, quinolinyloxy)phenoxy] gram without affecting the drug ^ The present invention also provides for the administration of the present invention: Musical activity. Treatments [Embodiment] Definitions and abbreviations As used above and throughout the specification of the present invention, the following abbreviations and symbols are understood to have the following inclusions = non-additional specification α α β β Ί Ί δ δ IV Intravenous PBS phosphate buffer Solution qs Appropriate amount, also gp, udan said < 疋 1 The above and the specification of the present invention are used 'unless otherwise stated, the following terms should be understood as having the following meanings: The term "active ingredient," as used herein, , (, "eingredient" and "principle" refer to (2R)_2-[4_(m啥linyloxy)phenoxy]propionic acid or a pharmaceutically acceptable salt thereof. 123610.doc 200817005 Cyclodextrin is contained a sugar in a circular hydrophobic central cavity and a hydrophilic outer surface. The term "cyclodextrin" as used herein may mean a cyclodextrin or a cyclodextrin derivative.

Capt1S〇l® is a sulfobutyl ether beta cyclodextrin available from CyDex, LLC. The term "hemolytic effect" refers to the alteration or destruction of red blood cells in a manner that releases heme into the bloodstream.

The term "solid tumor cancer" is used in its medically acceptable sense and does not include blood cancers such as leukemia. The present invention relates to a (2R)_2_[4_(7_ desert_2_quinolinyloxy) stearoxymorphic acid or a pharmaceutically acceptable salt thereof, a physiologically acceptable cyclodextrin (including the cyclodextrin group illusion and at least - the solubilizing agent of the medical (four) acceptable, aqueous formulation; the pH of the formulation is generally between about 4 and about 9' preferably between about 5 and about Between 8. "(2R)-2-[4_(7____Linyloxy)phenoxy]propionic acid or a strip: the salt of the party can be attached to about 1% to about A ratio of 5% (W/", for example, about /〇 to, ·, spoon 3 /0 (w/v) is present in the pharmaceutical formulation of the present invention. However: the formulation of the good contains 5% to about 5% 2% (w/v) is called 2_:-2-quinolinyloxy)phenoxy]propionic acid or a pharmaceutically acceptable salt thereof. 0 Any suitable cyclodextrin is subjected to the present invention, including the alpha ring. Dextrin% paste, cyclodextrin and heart ring paste and formula, such as sulfonamide _ production ... " temple clothing paste can be derivative derivative ring paste _ m soil, 'clothing; month 4 such as sulfobutyl Ether b cyclodextrin), hydroxyalkane meaning "1 (such as hydroxypropyl _β_cyclodextrin, burned cyclodextrin (for example, Base|... soil_β's smudge, sputum, dimethyl-β-cyclodextrin, three 123610.doc 200817005 thiol I cyclodextrin, diethyl + cyclodextrin) or Weiji Cyclodextrin (9) such as 'severyl thiol} cyclodextrin) and combinations thereof. Preferably, a butyl bromide or a hydroxypropyl β-cyclodextrin is used. The above cyclodextrin a is caused by a drug which reduces or prevents (2R)_2_[4_(7 winter 2 喧 基 yloxy) phenyloxy]propionic acid or a pharmaceutically acceptable salt thereof: hemolysis is possible .

Said cyclodextrin is incorporated in an amount of from about 1% to about 5% (w/v), preferably from about 5% to about 20/o (w/v), for example 1% (w/v) In the formulation. The cyclodextrin is preferably substantially effective in reducing hemolysis caused by (2R)_2_[4_(7-bromo-2-indolyloxy)phenoxy]propene or a pharmaceutically acceptable salt thereof The amount exists. "Permeability reduction" means that the cyclodextrin is effective to reduce the hemolysis of the active ingredient by about 30 〇 / 〇 or more relative to the hemolysis effect caused by the active ingredient in the absence of cyclodextrin | In the preferred aspect of the present invention, the 'nuclear dextrins are effective in reducing the hemolysis of the active ingredient relative to the amount of hemolysis caused by the active ingredient in the cyclodextrin. 5 % or more

The concentration of the active ingredient in the formulation is sufficient to substantially reduce the hemolysis of the active ingredient. Since (2R)-2 cases of 7_Mos _ 啥 基 基 ethoxy) phenoxypropionic acid have limited solubility, the pharmaceutical formulation contains at least one type of solubilizing agent to increase the active ingredient in the aqueous formulation. The solubility of _L (Moline: porphyrinoxy) phenoxy] propionic acid is an acidic compound which dissolves pH. (d) Suitable solubilizing agents include dissolving the ingredients and/or maintaining the solution in a physiologically acceptable range. 123610.doc 200817005 Pharmaceutically acceptable pH adjusting agents and/or buffers, such as acid/acids , such as citric acid, lactic acid, boric acid, acetic acid, phosphoric acid, hydrochloric acid, sulfuric acid and & C-hydrogen, and / alkaline agents, such as sodium hydroxide, citric acid steel, sodium borate, sodium acetate, sodium sulfate, Disodium hydrogen phosphate, trisodium phosphate, sodium carbonate, sodium hydrogencarbonate, hydroxymethylaminomethane, diethylamine, triethylamine and ammonium hydroxide. Preferably, the solubilizing agent is a physiologically acceptable buffer. In general, the buffer can both dissolve the active ingredient and maintain the pH of the formulation between about 4 and a force 9, preferably between about 5 and about 8. Preferred buffering agents of the invention include, for example, those selected from the group consisting of butyric acid/alkali metal succinate, citric acid/alkali metal citrate, tartaric acid/alkali metal tartrate, lactic acid/alkali metal lactate, butylene Acid/alkali metal maleate, acetic acid/alkali metal acetate, fumaric acid/alkali metal fumarate, methanesulfonic acid/alkali metal methanesulfonate, alkali metal sulfate, alkali Metal hydrogensulfate, phosphoric acid/monoalkali metal phosphate, base to genus % fee monohydrogen salt / alkali metal hydrogen hydride, tribasic metal citrate, alkali metal phosphate, alkali metal carbonate / alkali metal The buffer of bicarbonate is an alkali metal such as sodium or potassium in each of the above salts. Preferred buffering agents are * an early alkali metal phosphate/dibasic metal phosphate such as sodium dihydrogen phosphate / disodium hydrogen phosphate. Preferred buffer solutions include from about 0.01 to about 3 moles, more preferably from about 5 to about 0.2 moles of alkali metal phosphate dihydrogen phosphate/dibasic metal phosphate nitrogen salt (eg, sodium dihydrogen phosphate). A buffered aqueous solution of /disodium hydrogen phosphate). - Other solubilizing agents include pharmaceutically acceptable cosolvents (eg, ethanol, propanol and the like), surfactants (eg, p〇lys〇rbate 8〇 and I23610.doc -11 - 200817005 P0laxamer) and polymerization (eg, polyvinylpyrrolidone). Cyclodextrins can also be used to increase the solubility of the active ingredient in aqueous formulations. However, the ability of cyclodextrin to increase the solubility of active ingredients is related to pH. In addition to the active ingredient, cyclodextrin, solubilizer and water, the formulations of the present invention may also include tonicity modifiers such as electrolysis f (such as sodium chloride, chlorinated per acid), non-reducing sugars, and sugar alcohols (such as nectar). Sugar alcohol, sorbitol, xylitol or glycerol).

The pharmaceutical formulation of the present invention may be referred to as an anti-oxidant (e.g., sodium hydrogen sulfite, sodium thiosulfate, and ascorbic acid) in the case of 愔白白扛 & Formulations of the invention may also include one or more preservatives. The invention may be practiced using any suitable preservative, including, but not limited to, benzbnium, benzyl alcohol, methyl benzoic acid (tetra), phenyl age, and thimerosal. The amount of preservative is generally present in an amount of from about i.% to about 1%. The pharmaceutical formulations and compositions of the present invention can be prepared using conventional techniques known to those skilled in the art. The pharmaceutical formulations of the present invention preferably comprise a therapeutically effective amount of the active ingredient. The term "therapeutically effective amount" as used herein refers to the amount of active ingredient present in a pharmaceutical formulation administered in an amount sufficient to remedy the desired pharmacological or therapeutic effect and/or to prevent one of the treated diseases or The development of various symptoms or to a certain extent. The attending physician will consider a number of factors in determining the effective amount or dosage, including (but not limited to): the type of mammal; its size, degree of involvement, or age at which the preparation is administered, and general health; The severity of the disease; the response of individual patients; the mode of administration 123610.doc 200817005 The use of concomitant drugs; and its bioavailability characteristics; his relevant status of the selected dosing regimen. The pharmaceutical formulation of the invention is administered to a patient (9) including, but not limited to, a mammal, such as a human, by intravenous administration (including IV rapid injection and ίν infusion), intramuscular administration, and other parenteral routes. ). Pharmaceutical formulations are preferably administered by IV infusion.

Compositions of the present invention may be prepared by spray drying or drying to form a powder for reconstitution. The composition may be reconstituted with an aqueous liquid to form a parenteral coating. Another aspect of the invention is the inclusion of (2R)-2-[4-(7-ex-2-pyridyloxy)benzene. A composition of oxy]propionic acid or a pharmaceutically acceptable salt thereof, a physiologically acceptable cyclodextrin, and at least one solubilizing agent. The pharmaceutical formulations and/or compositions may be diluted prior to administration by conventional intravenous fluids known to those skilled in the art. Thus, a pharmaceutical formulation in a more concentrated form than the pharmaceutical formulations described above can be prepared, and the resulting formulation can then be diluted to the desired concentration. Another embodiment of the invention is directed to a dosage form comprising a pharmaceutical formulation as described herein. Each dose should contain an amount of active ingredient calculated to produce the desired therapeutic effect. Generally, the pharmaceutical formulation will be administered in a dosage unit containing the active ingredient in an amount of from about 1 mg to about 4000 mg, preferably from about 1 mg to about 2 mg, based on the weight of the composition. It will also be apparent to those skilled in the art that the pharmaceutical formulations of the present invention can be administered with other therapeutic and/or prophylactic agents and/or drugs compatible therewith. All components of the formulations of the present invention must be pharmaceutically acceptable. 123610.doc -13 - 200817005 As used herein, the "medical 孳璺 μ π μ / , acceptable" component is suitable for humans and / Or its substance: a component that has adverse side effects (such as toxicity, irritation, and allergic reaction) and an appropriate benefit/risk ratio. The present invention is further directed to the medical use of the pharmaceutical formulations of the present invention. 2 is called 2_[4_(7_bromo-2-(tetra)yloxy)phenoxy]propionic acid as an antitumor agent against domestic and bean tumors. Accordingly, the present invention provides a method of treating solid tumor cancer: 'oral therapy' which comprises administering to a patient in need of such treatment a therapeutically effective formulation of the present invention. Patients include primates, humans, dentate, large animals, _ animals, bovines, sheep, equines, porcines, goats and the like. Real It tumor cancer includes (but = 艮) colon cancer, breast cancer, prostate cancer, _ nest cancer, melanoma and pancreatic cancer. 0. The object of the present invention is to prepare a preparation for treating a solid tumor. Uses of medical products such as sinus gland, glucagon, "% cancer cancer, rainy gland cancer, Indian cancer, melanoma, and pancreatic cancer." The present invention also provides for the reduction of (2R)_2_[M7i2_(tetra)oxy a method for hemolytic activity of phenoxy-propionic acid or a pharmaceutically acceptable salt thereof, which comprises (2) 2_[4-(7-(4-hydroxy)oxy)propanoic acid The cyclodextrin is added to the composition of the salt or the acceptable salt thereof. The following examples will further illustrate the invention, but not limit the invention. In vitro research is carried out [column 1 · σο y , early A buffer formulation for in vitro hemolysis of canine red blood cells, both strength assessment.

The following study was conducted to evaluate the concentration of 1〇 mg/mL& 2〇 1T I236I0.doc

In vitro hemolysis is expressed as hemolysis by saponin. Hundred 200817005 (2R)_2]4-(7m«oxy)phenoxy-acid is hemolyzed in a solution of (u M pH 8 gamma buffer) Potential. Physiological saline (0.9% ci) was used as a negative pair &, and a specific element known as a hemolysis initiator (3% aqueous solution) was used as a positive control. The ratio of 9:1 is to mix the whole blood of the dog with the active ingredient in the vehicle and with the vehicle alone. The dog's whole blood is also 3% as a positive control at a ratio of 1:1 and 9:1. The saponin solution was mixed with physiological saline (0.99% NaC) as a negative control. After mixing, the tube was incubated at 3 rc for 30 minutes, followed by centrifugation (3 _/min) for 10 minutes. The heme concentrate was added. The supernatant was used to assess the in vitro hemolysis potential by uv/visible spectrophotometer (Genesis technologies). The percentage of hemolysis was calculated based on the results of the saponin sample. The results of this experiment are presented in Table! Hemolysis of canine red blood cells caused by sputum and 2 〇 solution, but not by separate agents. These results indicate Hemolysis induced by (2R)_2_[4_(7_ / odor-2-pylinyloxy)phenoxy]propionic acid at a concentration of 10 mg/mL and 20 mg/mL. Table 1 ··Hemolysis %* Fractions 1236l0.doc -15 - 200817005 Example 2: Assessment of in vitro hemolysis potential of canine red blood cells by formulations containing various additives This study was conducted to evaluate the hemolysis of drugs that have been reported to reduce the toxicity of certain other drugs. The various additives reduced the potential for hemolysis compared to the conventional phosphate buffer formulations described in Example 1. In particular, the following experiments assessed C concentrations of 1 〇 and 2 〇 mg/mL in various vehicles in vitro. 2 [4 (7- / odor-2-pyreneoxy) phenoxy] propionic acid on the hemolysis of canine whole blood '曰力. The aqueous solution tested was 2〇/〇 sucrose solution; 1% human albumin solution; 0.6% P〇l〇xamer 188 solution; 1% mannitol solution·, from 1% mannitol, 〇.5 A solution of % glycine and 〇·6% p〇1〇xamer (8), a 0.5% glycine solution; and a phosphate buffer solution as a control. The canine whole blood is mixed with the active ingredient in various media and mixed with a separate vehicle at a ratio of 1:1 and a ratio of 9:1. The whole (d) saponin solution was also mixed in the same ratio for use as a positive control. After incubation for 45 minutes at 3 n: τ, the sample was separated from the hemoglobin absorption rate of the resulting supernatant on a microplate reader (Dynex (4)) (10) __ 4.06. The results of the prime samples calculate the percentage of hemolysis. Hemoglobin Concentration is considered to be significant when whole blood and homologous plasma are more than 2-fold higher than the negative control value obtained by mixing whole blood to plasma (inherent plasma redness: the ratios cited). The results of the experiment are presented in Table 2. The drug-induced dissolution of other drugs can be reduced. == Use the previous description: 容血 f术基咖 I23610.doc 200817005 Table 2: Mean percentage of hemolysis* (n 2 12) Active ingredient concentration 0 mg/mL 1:1 ratio active ingredient concentration 10 mg/mL 1:1 ratio active ingredient concentration 20 mg/mL 1:1 ratio active ingredient concentration 0 mg/mL 9:1 ratio active ingredient concentration 10 mg/ mL 9:1 ratio Active ingredient concentration 20 mg/mL 9:1 ratio sucrose 2% 4.3% 47.4% 77.9% 5.2% 7.2% 13.0% Human albumin 1% 2.5% 38.4% 77.9% 6.5% 5.9% 15.0% Poloxamer 188 (0.6%) 3.2% 45.5% 72.4% 7.1% 7.9% 15.5% Mannitol 1% 4.7% 56.8% 82.2% 6,2% 6.1% 12.7% Mannitol 1%, Glycine 0.5%, Poloxamer 188 ( 0.6%) 2.0% 35.0% 82.1% 3.6% 5.6% 13.4% Glycine 0.5% 2.1% 34.2% 80,2% 3.6% 5.1% 15.0% Phosphate buffer 3.1% 29.5% 85,6% 5.2% 5.6% 12.8% Saponin solution 5% 100.0% - - 100.0% - - Patient plasma 2.7% - - 5.4% -

* In vitro hemolysis is expressed as a percentage of hemolysis caused by saponin. Example 3: Evaluation of in vitro hemolysis potential of canine red blood cells by formulations in various vehicles This study was also conducted to evaluate various parenteral vehicles. The potential for hemolysis is reduced compared to conventional phosphate buffer formulations. The following formulations were prepared: A) 0.1 M pH 8 phosphate. 20 mg/rnL active ingredient in buffer; B) 20 mg/mL active ingredient in 0.12 Μ sodium bicarbonate solution; and C) 0,1 M pH 20 mg/mL active ingredient in 10 citrate buffer plus 10 mg/mL NaCl 〇 physiological saline (0.9% NaCl) was used as a negative control, and saponin (3% aqueous solution) was used as a positive control. I23610.doc 200817005 The ratio of illusion: and the ratio of 9:1 mixes canine whole blood with the active ingredient in a vehicle and with a separate vehicle. Dog whole blood was also mixed at a ratio of 1:1 and 9·] with a 3% sin solution as a positive control and a physiological saline (0.9% NaC) as a negative control. After mixing, the tubes were incubated for 30 minutes at 3rc, followed by centrifugation (boom t/min) for 1 minute. The heme concentrate was added to the supernatant and the in vitro hemolysis potential was assessed by a uv/visible spectrophotometer (Genesis techn() I() gies). Based on interest

The results of the prime samples calculate the percentage of hemolysis. The result of this member is shown in Table 3. All three formulations elicited in vitro hemolysis of canine red blood cells. , Xuan ‘ ^ & blood effect index is expressed as the positive correlation of the saponin sample, the percentage of the value. Table 3: Percentage of Hemolysis* ------ Formulation Blood/Solution_ Ratio 20 mg/mL Active Ingredient A - n = 6 (Average) 1:1 23% 76.6% A n=6 (Average) 9: 1 1.6% 2.9% B n=6 (average) 1:1 20.0% 56.5% B ^^_ n=6 (average) ------ 9:1 ~—----- 3.1% —-- —_ 2.3% n-6 (average) -------- 1:1 ^--------. 2.4% L~_ 85.4% ---- 123610.doc 200817005 Formulation Blood/ Solution ratio does not contain / tongue-inducing agent 20 mg / mL Active ingredient C n = 6 (average) 9:1 U% 1.8% Physiological saline π-6 (average) 1:1 1.93% - Physiological saline 11 ==6 (average) 9:1 2.0% *In vitro hemolysis is expressed as the percentage of hemolysis caused by statin

Example 4: Evaluation of the in vitro hemolysis potential of canine red blood cells with a cyclodextrin-containing formulation. The following study was conducted to evaluate the formulation of a formulation containing Π) mg/mL of active ingredient in a 具有5M pH 7 phosphate buffer formulation with 10% (w/v) propyl propyl β-cyclodextrin. Reduce the potential for hemolysis. Will be physiological saline (〇·9%

NaCl was used as a negative control, and saponin (3% aqueous solution) was used as a positive control. The canine whole blood is mixed with the active ingredient in a vehicle at a ratio of 1.1 and a ratio of 9:1 and mixed with a separate vehicle. Dog whole blood was also mixed with a 3% saponin solution as a positive control and a physiological saline (0.9% NaCl) as a negative control at a ratio of 1:1 and Μ. After mixing, the tubes were incubated at 3n: for 30 minutes, followed by centrifugation (3 〇〇〇 in) 10 4 4 gram of hemoglobin concentrate added to the supernatant for UV, visible spectrophotometer (Genesis teehnQlGgies ) Assessment of in vitro hemolysis potential. The percentage of hemolysis was calculated based on the results of the saponin sample. The results of this test are presented in Table 4. The present invention is a 0-1 heart-shaped 10 mg/mL·cyclodextrin 123610.doc -19- 200817005 The formulation does not cause the in vitro dissolution of blood of canine red blood cells. Table 4: Percentage of hemolysis* Blood/solution ratio 10 mg/mL active ingredient ----- No active ingredient Physiological saline 1:1, n=6 (average) 1.8% 0.2% ------ - 1.8% 9:1, n=6 (average) 0.5% 0.8% 1.2%

* In vitro hemolysis is expressed as a percentage of hemolysis caused by saponin. Example 5. In vitro hemolysis evaluation of cyclodextrin formulations with human blood and plasma. The following experiment evaluates the cyclodextrin formulation of the present invention in vivo. Potential for external hemolysis to prepare active ingredients at concentrations of 2 mg/mL, 5 mg/mL and i 〇mg/mL in vehicle (I〇% Captis〇iV/v in 0.05 Μ discate buffer) The solution was used as a test solution. For each solution, the ratio of blood tested to test solution and blood to vehicle was 1:1 and 9:1. Whole blood sputum is mixed as a positive contrast. Place all the tubes in the pit for a few minutes, then centrifuge (5) (1) g〇5哉) for 5 minutes. In the micro "U (Dynex: ΐ: Γ 5 MRX reVel - concentrated hemoglobin absorption rate. Base: the results of the sputum sample to calculate the percentage value of hemolysis than the measurement of whole blood and homologous plasma with $ and $, _ / _ Clamp Zhao Zhaogu} A negative t... value obtained by this combination is considered to be significant. Hemolysis is significant. 123610.doc -20- 200817005, Capitol® vehicle alone and containing ι〇mg/mL The active ingredient containing the Captisol® formulation did not elicit the hemolysis of human whole blood. a Example 6 • In vitro hemolysis assessment of formulations of various drug concentrations, buffer pH values, and molar concentrations and cyclodextrin concentrations

Table 5 shows the solubility data for various buffer pH and molar concentrations, with and without the tongue component of Captisol. In the case of _ ' 〇 _ still μ buffer strength, when the solubility of the active ingredient is low, i〇% captis〇i (g) is added to increase the dissolution of the active ingredient by more than 2 times. The solubility of the active ingredient in the formulation increases as the pH of the buffer or the molar concentration increases. However, Captis was added at a lower pH or Moire tear. The solubility was increased to a lesser extent. No increase in the degree of solution was observed in the pH 8 〇·i M buffer. Table 5 • Various buffers Liquid pH and phosphate buffer strength and solubility (mg/mL;) pH 7.0 pH 7.5 t^T Τ 〇a 0.05 Μ 4.8 , 8.6 pH 〇.0 0·05 Μ and 10% CaptisoP 10.3 13.4 _L〇:6 0.1 Μ 8.6 17.2 --L5.0 〇·1 M and 10% Captisol8 15.9 19.0 L 21.3 ... limb m 怙 怙 研究 研究 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲 缓冲= The method for assessing hemolysis was the same as that described in Example 2. The ratio of the two dilutions and the percentage of hemolysis were observed. 1236I0.doc 200817005 Table 6: Formulation number Active ingredient concentration (mg/mL) PBS Mo Ear concentration (M) — PH value Captisol® % (w/v) Mean hemolysis 1:1 blood> Valley ratio 9:1 Blood roll Pan 1* Bu Cheng 1 9 0.1 8.0 0 23 7 /廿/代CCl ο 〇2 9 0.05 7.0 10 4.2 0 〇3 9 0.1 8.0 10 3.2 «3 〇Ο 4 18 0.1 8.0 0 74 0 Q < 5 18 0.1 ”·0 10 14.3 〇.!) Λ *7 6 18 0.1 ”.0 20 2.7 τ*. J 9 Q 7 0 0.05 7.0 10 2.2 0 Λ 8 0 0.1 8.0 10 3.2 '•U 9 9 9 0 0.1 —----- —8·0 20 4.7 Μ · W 2·8 Expressing in vitro hemolysis as a hundred hemolytic effect induced by saponin

Fractions The formulation of the active ingredient concentration of 9 and 8 mg/mL in the absence of CaptisoP initiated bathing (formulation numbers 1 and 4). Formulations with a concentration of 1 mg% Captis® (g) of active ingredient of 9 mg/mL provide effective hemolysis protection at different pH and buffer molar concentrations (Formulation Nos. 2 and 3). For formulations with an active ingredient concentration of 18 mg/mL, some hemolysis was observed with a 10% Captisol0 pH of 8 (Formulation No. 5). However, no hemolysis was observed for formulations with the same active ingredient concentration, pH and molar concentration but with 20% Captisol0 (formulation number 6). 123610.doc -22- 200817005 These results indicate that the charge of CaptisGl8 and the ratio of Captisw to drug are important to provide hemolysis protection. In the research paradigm, the rhythm of the buffer or the concentration of the material (4) is the poetic degree of the active ingredient and the increase of Capl〇1', but it only affects the hemolysis protection of Captisol®. In vivo study Example 7: In vivo in vivo study with a 30 minute infusion (10) salt buffer formulation administered to a male male, only a beagle dog, by a single intravenous infusion over 3 minutes. A solution of the active ingredient in a concentration of 1 〇 mg/mI^2 〇/虹 in a buffer of 〇._acidate to obtain a total exposure of 25 and 50: g/kg, respectively. Samples were taken at 1 A for plasma content measurements at the following intervals: end of infusion (G), 3 G minutes after end of infusion, i hours, 3 hours, 6 hours, and 24 hours.

RESULTS: At time 0, 30 minutes after infusion (all animals), i hours (male animals treated with mg/kg and two animals treated at 5 mg/kg), 3 hours (treated at 50 mg/kg) The hemolysis of plasma samples was visualized by two animals) and 6 hours (female animals treated with 5 。). Example 8: In vivo study of phosphate buffer formulations or cyclodextrin formulations of the invention

A single concentration of 0, 2.5, 5, and 10 mg/mL of the active ingredient in 〇1 M phosphate buffer was administered to one male and one female female by a single intravenous infusion over a period of one hour. . The doses were 〇 (control), 1〇〇, 2〇〇, and 4(10) mg/kg. Results • On the day of infusion, 6 of the 1 males at the 400 mg/kg dose was 123610.doc -23 · 200817005 only and ίο Eight of only females were observed to be most likely to have discolored urine (red/brown) caused by the hemolysis potential of the active ingredient. In a study conducted in rats at a dose of 1 〇〇, 200, 300, and 350 mg/kg using a formulation with CaptisoP, the first! Only 3 out of 12 females in I and only k in the 12 females on day 2 observed k: color (red) urine. This dose was obtained in rats using the highest concentration (1 〇 mg/mL) and very high volume administration (Μ mL/kg). Not observed in dogs using Captisol® formulations at doses of 1〇, 50, and 75 mg/kg (maximum concentration of 7.5 mg/mL, administration volume of 1〇mL/kg) To hemolysis. Example 9 - In vivo study of the dog with the cyclodextrin formulation of the present invention The active ingredient was administered to a female Miguel dog for 1 hour by a single intravenous infusion with 10% hydroxy-propyl β-cyclodextrin A solution (1 mg/mL) of an aqueous solution of 0.05 M pH 7 phosphate buffer. The dose is 50 mg/kg. Samples were taken at 1 hour intervals as follows: end of infusion (0), 30 minutes after end of infusion, 1 hour, 3 hours, 6 hours, and 24 hours. Results: In vitro hemolysis was not observed in the blood samples. Example 1 〇: The following is an example of a pharmaceutical formulation of the present invention: 8.00 mg 100 mg 2.92 mg 10.1 mg Appropriate amount to 1 ml Material active ingredient sulfobutyl ether β-cyclodextrin dihydrogen phosphate dihydrogen sodium dodecanoic acid Hydrogen two steel water 123610.doc 24- 200817005 Material _ active ingredient sulfobutyl ether β cyclodextrin monohydrate sodium dihydrogen phosphate anhydrous sodium hydrogenate disodium water * _ 10.0 mg 100 mg 2.5 mg 3.9 mg appropriate amount to 1 ml

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Claims (1)

200817005 X. Patent application scope: 1. A pharmaceutically acceptable water-based, lion-like compound that contains (2R)-2_[4_(7-bromo-2-quinolyloxy) stupid Its 1 # mercapto]propionic acid or a pharmaceutically acceptable salt thereof, a physiologically acceptable cyclodextrin, and at least one solubilizing agent. 2. The formulation of claim 1, wherein 兮〇T ...... 2-quinolinyloxy)phenoxy]propionic acid or its medicinal preparation W / 永上上的的盐系系% to about 5% (w/v) is present. 3. The formulation of claim 1, wherein the cyclodextrin is selected from the group consisting of alpha-cyclodextrin, beta dextrin, gamma-cyclodextrin, "dextrin and its derivatives. The formulation of claim 3, wherein the product is selected from the group consisting of a sulfoalkyl ether cyclodextrin, a hydroxyalkyl cyclodextrin, a decyl group dextrin, and a carboxyalkyl cyclodextrin. 5. As in the formulation of claim 4, wherein the 哕 恤 她 & &" espresso is selected from the group consisting of sulfobutyl ether β-cyclodextrin and hydroxy-propyl cyclodextrin. The formulation of claim 5, wherein the gentleman/, Τ 4 dextrin is sulfobutyl ether cyclodextrin. 7. The formulation of claim 6, wherein the cyclodextrin is (iv) (v) 8. 8. The formulation of 1 wherein the cyclodextrin is present in an amount of from about 1% to about 50% (w/v). 9. The formulation of claim 8, wherein the sputum is 4% dextran. 5% to about 20% (w/v) is present. 10. The formulation of claim 8 wherein the cyclodextrin is present in an amount of about 10% (w/v). a formulation wherein the solubilizing agent is physiologically The receiving buffer 123610.doc 200817005 _. 12. The requested item "the formulation, wherein the buffer concentration is from about 〇i μ billion to about 25 billion · [mu]. To 13. The formulation as claimed in claim 1, wherein the buffer is a monoalkali metal phosphate/bimetal phosphate buffer. 14. The formulation of claim 1 which has a pH of between about 5.0 and about 80. B's 15. A formulation as claimed in the formula, which additionally comprises a tonicity modifying agent. 16. A formulation as claimed, which additionally comprises one or more physiologically acceptable preservatives. The formulation of claim 17 further comprising a pharmaceutically acceptable agent. Further η. a composition comprising (211)_2-[4_(7 22_啥琳-yloxy)phenoxy]propionic acid or a pharmaceutically acceptable salt thereof, physiologically acceptable Cyclodextrin and at least one solubilizer. 1 9 · The composition of the syllabus of the syllabus of the '18' θ 咏 paste wheel is sulfobutyl ether β-cyclodextrin 0 20. A >. A method of treating solid tumor cancer, which comprises administering a therapeutically effective amount to a need for the treatment; Pharmaceutical formulations. . The method of the lunar member 20 wherein the solid tumor cancer is selected from the group consisting of colon cancer, ovarian cancer, melanoma, and pancreatic cancer. 2 2 · A use of the ingredients of claim 1, art, and sirloin for the manufacture of a medical product for the treatment of solid tumor cancer. 123610.doc 200817005 23. A method for reducing (2R)-2-[4-(7-bromo-I-quinolinyloxy)phenoxy]propionic acid or a pharmaceutically acceptable salt hemolytic activity thereof, comprising A fine is added to the composition containing (2R)j-[4-(7-indol-2-yllinyloxy)phenoxy]propionic acid or a pharmaceutically acceptable salt thereof. A physiologically acceptable cyclodextrin is obtained from the method of claim 23, wherein the cyclodextrin and the propyl-propyl-cyclodextrin are composed of a free radical - a butyl group - 123610.doc 200817005 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: Br (I) 5 123610.doc